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In vivo and in vitro Studies of Adaptor-clathrin Interaction
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CDK5 inhibits the clathrin-dependent internalization of TRPV1 by phosphorylating the clathrin adaptor protein AP2μ2

Jiao Liu1,2, Junxia Du3, Yun Wang4,5

  • 1Center of Medical and Health Analysis, Peking University Health Science Center, Beijing 100191, China.

Science Signaling
|June 13, 2019
PubMed

Insights

Constitutive internalization of the TRPV1 channel depends on AP2μ2. Cyclin-dependent kinase 5 (CDK5) reduces this internalization, promoting inflammatory pain. Inhibiting CDK5 may offer new pain relief strategies.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Transient receptor potential vanilloid 1 (TRPV1) channels are crucial for pain sensation and are regulated by kinases.
  • Previous studies primarily focused on agonist-induced TRPV1 internalization.

Purpose of the Study:

  • To elucidate the mechanism of constitutive TRPV1 internalization.
  • To investigate the role of cyclin-dependent kinase 5 (CDK5) in regulating TRPV1 trafficking and inflammatory pain.

Main Methods:

  • Investigated TRPV1 internalization pathways, including clathrin, dynamin, and adaptor protein complex 2 (AP2).
  • Examined the interaction between AP2μ2 and TRPV1.
  • Assessed the effect of CDK5 phosphorylation of AP2μ2 on TRPV1 internalization.
  • Utilized a cell-penetrating peptide to inhibit CDK5 activity in vivo and evaluated its effect on inflammatory pain in a rat model.

Main Results:

  • Constitutive TRPV1 internalization is dependent on clathrin, dynamin, and AP2.
  • The μ2 subunit of AP2 (AP2μ2) directly interacts with TRPV1 and is essential for its internalization.
  • CDK5 phosphorylates AP2μ2 at Ser45, weakening the TRPV1-AP2μ2 interaction and decreasing TRPV1 internalization.
  • Inhibition of CDK5 phosphorylation of AP2μ2 increased surface TRPV1 and reduced inflammatory thermal hyperalgesia in rats.

Conclusions:

  • A novel mechanism for TRPV1 constitutive internalization involving AP2μ2 is described.
  • CDK5 negatively regulates TRPV1 internalization by phosphorylating AP2μ2.
  • CDK5 promotes inflammatory thermal hyperalgesia by reducing TRPV1 internalization, identifying CDK5 as a potential therapeutic target for pain management.

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